Abstract
Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.
Highlights
Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD)
We observed that the presence of obstructive CAD is significantly and independently associated with lower plasma free EET levels
The association between obstructive CAD and lower EET levels a) correlates with lower CYP epoxygenase metabolic function, but not higher soluble epoxide hydrolase (sEH) metabolic function and b) is significantly more pronounced than other eicosanoid metabolism pathways. These findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis
Summary
Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). Quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways These findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. The discovery of biomarkers involved in the pathogenesis of CAD offers considerable promise to facilitate the development of novel therapeutics and identify subsets of highrisk patients who may derive the greatest benefit from therapy [2] In addition to their role as xenobiotic metabolizing enzymes, cytochromes P450 (CYPs) metabolize fatty acids to bioactive lipids that regulate numerous cellular and physiological processes relevant to the pathogenesis of CAD [3].
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